This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
EP-A-0 126 311, EP-A-0 376 524, EP-A-0 205 292, EP-A-0 250 077, EP-A-0 093 535, EP-A-0 150 202, EP-A-0 076 075 and WO/89/05808 (Beecham Group plc) describe certain benzopyran derivatives which possess anti-hypertensive activity.
EP-A-0 430 621 and EP-A-0 385 584 (Beecham Group plc) describe the resolution of certain intermediates useful in the preparation of the compounds described in the above mentined patent applications.
EP-A-0 139 992 (Beecham Group plc) describes certain benzopyran derivatives which have cis isomerism at position 3 and 4 which compounds are described as possessing anti-hypertensive activity.
EP-A-0 587 645, EP-A-0 673 373, EP-A-0 673 374, EP-A-0 673 248, EP-A-0 674 519, WO95/34545, WO95/34547 and WO95/34546 (SmithKline Beecham plc) describe groups of benzopyran compounds possessing inter alia anti-convulsant activity.
This invention is based on the finding that further benzopyran compounds of formula (I) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, amyotrophic lateral sclerosis (ALS), ataxias, muscular rigidity (spasticity), and/or temporomandibular joint dysfunction.
Accordingly, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt or solvate thereof: 
in which
R1 is C1-6 alkylcarbonyl in which the alkyl group is substituted by OH;
R2 is hydrogen or C3-8 cycloalkyl, C1-6 alkyl optionally interrupted by oxygen or substituted by hydroxy, C1-6 alkoxy or substituted aminocarbonyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, CF3S, or a group CF3xe2x80x94Axe2x80x94, where A is xe2x80x94CF2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, CH(OH), SO2, SO, CH2xe2x80x94O, or CONH, or a group CF2Hxe2x80x94Axe2x80x2xe2x80x94 where Axe2x80x2 is oxygen, sulfur, SO, SO2, CF2 or CFH; trifluoromethoxy, C1-6 alkylsulfinyl, perfluoro C2-6 alkylsulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfinyl, C1-6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl in which any aromatic moiety is optionally substituted, C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercapto C2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C1-6 alkyl groups, or C1-6 alkylsulfinylamino, C1-6 alkylsulfonylamino, C1-6 alkoxysulfinylamino or C1-6 alkoxysulfonylamino, or ethylenyl terminally substituted by C1-6 alkylcarbonyl, nitro or cyano, or xe2x80x94C(C1-6 alkyl)NOH or xe2x80x94C(C1-6 alkyl)NNH2,
Ra is hydrogen, halogen, nitro; C1-4 alkylcarbonyl, C1-4 alkyl; aryl C1-4 alkyl, aryl C1-4 alkenyl, heteroaryl C1-4 alkyl or heteroaryl C1-4 alkenyl,
Rb is hydrogen, halogen, nitro; C1-4 alkylcarbonyl or C1-4 alkyl; and in which any aryl or heteroaryl or alkyl moiety associated with Ra or Rb are optionally substituted;
one of R3 and R4 is hydrogen or C1-4 alkyl and the other is C1-4 alkyl, CF3 or CH2Xa where Xa is fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, xe2x80x94Sxe2x80x94C1-4 alkyl, nitro, amino optionally substituted by one or two C1-4 alkyl groups; cyano or C1-4 alkoxycarbonyl;
or R3 and R4 together are C2-5 polymethylene optionally substituted by C1-4 alkyl;
R5 is C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy or C1-6 alkoxy and R6 and R9 are hydrogen or R5 is hydroxy and R6 and R9 are independently hydrogen or C1-2 alkyl;
R7 is heteroaryl or phenyl; both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C1-4 alkyl, cyano, azido, C1-4 alkyl, C1-4 alkoxy, trifluoromethoxy, trifluoromethyl; optionally substituted aryloxy or heteroaryloxy; C1-4 alkoxy substituted by one or more halogens; amino substituted by C1-4 alkanoyl, aroyl, aryl, phenylsulfonyl or C1-4 alkylsulfonyl; C1-4 alkyl substituted by one or more halogens or alkoxy; phenylsulfonyl C1-4 alkyl sulfonyl, aminosulfonyl in which the amino group is optionally substituted by C1-4 alkyl; CONH2 in which the amino group is optionally substituted by C1-4 alkyl;
R8 is hydrogen; C1-6 alkyl, OR16 or NHCOR17 wherein R16 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl and R17 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di C1-6 alkyl amino, amino, amino-C-1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6-alkyl, aryl or heteroaryl;
or R7 and R8 together form a C3-4 alkylene group;
and the R8xe2x80x94Nxe2x80x94COxe2x80x94R7 group is cis or trans to the R5 group.
A preferred group of compounds are of formula (IA) 
i.e. R2, R6, R8, R9, Ra and Rb are hydrogen, R5 is hydroxyl, R3 and R4 are both methyl, or one of R3 and R4 is methyl and the other of R3 and R4 is hydroxymethyl, and the R7CONH group is cis or trans to the R5 hydroxyl group.
Preferably R7 is phenyl or heteroaryl which may be optionally substituted by up to three substituents independently selected from:
bromo, chloro, fluoro, iodo, nitro, amino optionally substituted once or twice by C1-4 alkyl, cyano, azido, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl or trifluoromethoxy.
More preferably R7 is phenyl substituted by one or two groups independently selected from chlorine and fluorine.
It should be appreciated that the compounds of formula (I) may have chiral carbon atoms at positions 2, 3 or 4 and therefore may exist as enantiomers. The present invention extends to each enantiomer and to mixtures thereof including racemates. It should further be appreciated that particular enantiomeric forms are preferred for different utilities, thus for utilities other than sub-arachnoid haemorrhage or neural shock the 3R, 4S and 3S, 4S enantiomers are preferred, however, for sub-arachnoid haemorrhage or neural shock the 3S, 4R and 3R, 4R enantiomers are preferred.
The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt thereof as hereinbefore defined which exists predominantly in the cis 3S, 4S or trans 3R, 4S enantiomeric form.
The term xe2x80x9cexists predominantly in the 3S, 4S enantiomeric formxe2x80x9d means that there is greater than 50% of the 3S, 4S enantiomer present compared to the 3R, 4R enantiomer. More preferably there is greater than 60% of the 3S, 4S enantiomer present, yet more preferably greater than 70% of the 3S, 4S enantiomer present, even more preferably greater than 80% of the 3S, 4S enantiomer present and more preferably still greater than 90% of the 3S, 4S enantiomer present. Most preferably there is greater than 95% of the 3S, 4S enantiomer compound relative to the 3R, 4R enantiomer.
The term xe2x80x9cexists predominantly in the 3R, 4S enantiomeric formxe2x80x9d means that there is greater than 50% of the 3R, 4S enantiomer present compared to the 3S, 4R enantiomer. More preferably there is greater than 60% of the 3R, 4S enantiomer present, yet more preferably greater than 70% of the 3R, 4S enantiomer present, even more preferably greater than 80% of the 3R, 4S enantiomer present and more preferably still greater than 90% of the 3R, 4S enantiomer present. Most preferably there is greater than 95% of the 3R, 4S enantiomer compound relative to the 3S, 4R enantiomer.
Examples of compounds of formula (I) are:
(3R,4S)-4-(3,5-difluorobenzamido)-3,4-dihydro-2,2-dimethyl-3-hydroxy-6-(2-hydroxyacetyl)-2H-1-benzopyran
(3S,4S)-4-(3-chloro-4-fluorobenzamido)-3,4-dihydro-2,2-dimethyl-3-hydroxy-6-(2-hydroxyacetyl)-2H-1-benzopyran
(3R,4S)-4-(4-fluorobenzamido)-3,4-dihydro-2,2-dimethyl-3-hydroxy-6-(2-hydroxyacetyl)-2H-1-benzopyran
When synthesised, these compounds may be isolated in salt form, such as the hydrochloride or trifluoroacetate, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts. The compounds and their salts may be obtained as solvates, such as hydrates, and these also form part of this invention.
The above compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
The administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal, topical or transdermal administration.
An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
It is greatly preferred that the compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral, including sub-lingual, rectal, topical or parenteral (especially intravenous) composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
Accordingly, the present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides a method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction.
In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction.
The present invention also provides a process for the preparation of compounds of formula (I), which comprises treating a compound of formula (II): 
in which Rx is a C1-6alkyl carbonyl group, and R2A, R3A, R4A, R5A, R6A, R7A, R8A, R9A, RaA and RbA are R2, R3, R4, R5, R6, R7, R8, R9, Ra, and Rb as defined for formula (I) or a group or groups convertible to R2, R3, R4, R5, R6, R7, R8, R9, Ra and Rb, with a reagent or sequence of reagents which introduces a hydroxyl group into the alkyl group of Rx;
and where required converting an R2A, R3A, R4A, R5A, R6A, R7A, R8A, R9A, RaA or RbA group to a R2, R3, R4, R5, R6, R7, R8, R9, Ra or Rb group,
converting one R2, R3, R4, R5, R6, R7, R8, R9, Ra or Rb group to another R2, R3, R4, R5, R6, R7, R8, R9, Ra or Rb group,
converting a salt product to the free base or another pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt.
For example, the compounds of formula (II) may be reacted with [bis(trifluoroacetoxy)iodo]benzene, by heating under reflux in a suitable solvent.
Conversions of an R2A, etc., group to an R2, etc group typically arise when a protecting group is needed during the above reaction or during the preparation of the reactants by the procedures described below, or when it is easier to introduce a bulky or reactive substituent at the end of a synthetic sequence. Interconversion of one R2, etc., group to another typically arises when one compound of formula (I) is used as the precursor of another compound of formula (I).
The group R1, once formed, may also require protection with a protecting group during the conversion of R2A etc to R2 etc and/or the conversion of one R2 etc to another R2 etc.
The preparation of compounds of formula (II) is described in the above referenced Beecham Group and SmithKline Beecham patent applications, with especial reference to EP-A-0766075, EP-A-0126311, WO 94/13656 and WO 95/34545.
More particularly, compounds of formula (II) may be prepared by reacting a compound of formula (III) 
with a compound of formula (IV)
R7ACO.Lxe2x80x83xe2x80x83(IV)
in which L is OH, acyloxy, or a halogen, especially Cl or Br, under conventional conditions for coupling carboxylic acids or active derivatives thereof with amines. For example, see the conditions for the similar coupling in Examples 2,5 and 6 in WO 94/13656.
As indicated previously, compounds of formula (I) may be in the trans or cis configuration as regards the position of the group R8NCOR7 relative to the group R5, and the configuration of the compounds of formula (I) will follow from the configuration of the precursor of formula (II). Compounds of formula (II) may be prepared in the trans form using procedures which are generally described in EP-0126311, EP-0376524, EP-205292, EP-0250077, EP-0093535, EP-0150202, EP-0076075 and WO 89/05808.
The cis compounds may be prepared by procedures generally described in or analogous to those described in EP-A-0139992. Also cis compounds may be prepared from the corresponding trans compounds by the procedure described in WO 94/13657 when R5 is hydroxy and R8 is hydrogen, by treatment with trifluoromethane sulphonic anhydride to form an intermediate cis-oxazoline compound.
It should be appreciated that racemates of formula (I) or formula (II) may be resolved, or enantiomerically purified compounds of formula (I) or formula (II) may be prepared using procedures conventional in the art, and in particular using the procedures outlined in EP-A-0430631 and EP-A-0355584.
It is preferred that the compounds of formula (II) are prepared in the required enantiomeric form by forming a chirally pure epoxide using catalysts and conditions generally outlined in WO 91/14694 or WO 93/17026 and thereafter converting the epoxides to the required compound of formula (II) using procedures outlined herein.
Compounds of formula (III) may be prepared by treating a compound of formula (V) 
with ammonium hydroxide.
The epoxy compounds of formula (V) may be prepared as disclosed in EP-A-0076075 or GB-A-1511187, for example from compounds of formula (VI) 
Compounds of formula (VI) may be prepared as in GB-A-1511187 or using procedures analogous to those described therein.
Compounds of formula (IV) are commercially available carboxylic acids or acid halides or may be prepared by further substitution of commercially available compounds using conventional procedures or by oxidation of corresponding alcohols. For the preferred substituted phenyl compounds, substituted benzoic acids that are not readily available may be prepared by oxidation of corresponding substituted benzyl alcohols. Alternatively benzoic acids can be prepared from correpondingly substituted phenols, for example by formation of the acetate, conversion to an acetophenone and then to the desired acid.